Recent evidence documents relationships between the immune, endocrine and neural systems. A molecular basis for these interactions is an embryonic commonality and the production of similar signal molecules. Therefore manifestations and alterations in one systems result in manifestations and alterations in the other systems. In vivo support for this concept are the reports that athymic or thymectomized mice present with severe endocrine disorders such as hypothyroidism. Thyrotropin (TSH) is a pituitary molecule regulated positively by thyrotropin releasing hormone (TRH) and negatively by feedback from the thyroid gland in the form of thyroid hormones, T3 and T4. Recent studies have documented that the immune system both produces immunoreactive TSH as well responds to TSH and TRH. Based on the afforementioned rationale, we have postulated that there exists a hypothalamic-lymphoid-thyroid (HLT) axis. We have partially developed and preliminarily tested a novel in vitro system (hypothalamic-pituitary- thyroid --HPT axis). We have shown that cells of the immune system respond in vitro to TRH by releasing ir-TSH. We have also shown in a small sample that in individuals with a reduced or "blunted" in vivo TSH response to exogenous TRH administration, there is generally a blunted in vitro ir-TSH response. Similarily, for those individuals with a normal in vivo response to TRH, there is also an increase in vitro ir-TSH production. Based on our preliminary data, we have gone one step further in our hypothesis and proposed that leukocytes, serving as models of the HPT axis, reflect defects in the neuroendocrine axis as similar defects in the HLT axis. In this project, we plan to further characterize the parallelness of the HLT with the HPT axis by using inbred mouse models of defined thyroid and T cell function. Using this well controlled animal model system, we may ask mechanistic questions concerning the regulation of the genes for ir-TSH and the status of putative TRH receptors on cells of the immune system in relation to their putative counterparts in the neuroendocrine system. This type of system will establish the validity of using the HLT as a peripheral model for the HPT axis. This system may have ramifications in endocrinology, immunology as well as neuroscience and neurobehavior. Our system may be useful for studying the molecular and mechanistic basis for interactions between the immune and neuroendocrine systems. This research may provide a rationale for holistic approaches to mental health and susceptibility to endocrine disorder, infection, cancer and autoimmune disease processes.